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Currently, complete surgical resection provides the only potential for long-term cure of PDA but only a minority of patients have tumors that are amenable to surgery [Shaib et al. 2006]. This is due to the fact that, upon diagnosis, tumors have generally spread to involve critical abdominal vessels as well as adjacent organs. Significant advances have been made in the technical aspects of surgical resection with decreases in short-term morbidity and mortality at major centers [Winter et al. 2012]. Yet even in the most experienced centers, long-term survival after surgery is poor [Farnell et al. 2005; Ferrone et al. 2012], with tumors recurring in virtually all patients [Allison et al. 1998]. Due to the high rate of recurrence, local targeted therapy with radiation has been suggested following surgery. However, controlled studies of the long-term impact of adjuvant radiation therapy have proved inconclusive to date [Neoptolemos et al. 2004]. The cytotoxic effect of radiation therapy relies in part on the presence of oxygen [Harrison et al. 2002]. However, intraoperative oxygen measurements on human patients have found that these tumors are extremely hypoxic [Koong et al. 2000], which may contribute to the limited impact of this modality.

The limited long-term efficacy of surgery and adjuvant radiation therapy has led many to conclude that residual tumor tissue remains even in the case of complete surgical resection with no evidence of residual tumor. One possible explanation is that of ‘field effect’ mutations that may affect otherwise normal appearing cells present in the residual pancreatic tissue. Alternatively, PDA may simply metastasize at a microscopic level at a very early stage. Indeed, provocative data in a genetically engineered mouse model of PDA suggest that mutant cells may delaminate from the pancreatic epithelium and enter circulation in the very early stages of tumorigenesis even prior to the development of an overt carcinoma [Rhim et al. 2012]. If this is true, then PDA should be considered an inherently metastatic disease for which local therapy is simply a delaying action. This also highlights the importance of identifying chemotherapeutic agents that effectively target microscopic metastases. It is notable that mutation evolution analysis based on deep sequencing of human pancreatic tumor samples has suggested a long latency period for PDA, estimating that it may take an average of 17 years for a tumor to evolve from a single common progenitor [Yachida et al. 2010]. However, a computational modeling study is consistent with the notion that PDA metastasizes early in disease [Haeno et al. 2012].

Clinical data of therapeutic efforts following resection of PDA are summarized in Table 1. These trials are consistent in demonstrating a small benefit when assessing recurrence but limited impact on long-term survival regardless of the intervention [Neoptolemos et al. 2004, 2010; Stocken et al. 2005; Oettle et al. 2007]. The modest achievements of adjuvant therapy compare poorly with the experience in other common cancers. Unfortunately PDA cells display broad and intractable resistance to chemotherapy, the subject of the remainder of this review.